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Genetics in Medicine : Official Journal... Jun 2024The aim of this study is to identify likely pathogenic (LP) and pathogenic (P) genetic results for autism that can be returned to participants in SPARK...
PURPOSE
The aim of this study is to identify likely pathogenic (LP) and pathogenic (P) genetic results for autism that can be returned to participants in SPARK (SPARKforAutism.org): a large recontactable cohort of people with autism in the United States. We also describe the process to return these clinically confirmed genetic findings.
METHODS
We present results from microarray genotyping and exome sequencing (ES) of 21,532 individuals with autism and 17,785 of their parents. We returned LP and P (American College of Medical genetics (ACMG) criteria) copy number variants (CNVs), chromosomal aneuploidies, and variants in genes with strong evidence of association with autism and intellectual disability.
RESULTS
We identified 1903 'returnable' LP/P variants in 1861 individuals with autism (8.6%). 89.5% of these variants were not known to participants. The diagnostic genetic result was returned to 589 participants (53% of those contacted). Features associated with a higher probability of having a returnable result include cognitive and medically complex features, being female, being White (versus non-White) and being diagnosed more than 20 years ago. We also find results among autistics across the spectrum, as well as in transmitting parents with neuropsychiatric features but no autism diagnosis.
CONCLUSION
SPARK offers an opportunity to assess returnable results among autistic people who have not been ascertained clinically. SPARK also provides practical experience returning genetic results for a behavioral condition at a large scale.
PubMed: 38958063
DOI: 10.1016/j.gim.2024.101202 -
Pediatric Obesity Jul 2024This study identified metabolite modules associated with adiposity and body fat distribution in childhood using gold-standard measurements.
OBJECTIVE
This study identified metabolite modules associated with adiposity and body fat distribution in childhood using gold-standard measurements.
METHODS
We used cross-sectional data from 329 children at mid-childhood (age 5.3 ± 0.3 years; BMI 15.7 ± 1.5 kg/m) from the Genetics of Glucose regulation in Gestation and Growth (Gen3G), a prospective pre-birth cohort. We quantified 1038 plasma metabolites and measured body composition using the gold-standard dual-energy x-ray absorptiometry (DXA), in addition to skinfold, waist circumference, and BMI. We applied weighted-correlation network analysis to identify a network of highly correlated metabolite modules. Spearman's partial correlations were applied to determine the associations of adiposity with metabolite modules and individual metabolites with false discovery rate (FDR) correction.
RESULTS
We identified a 'green' module of 120 metabolites, primarily comprised of lipids (mostly sphingomyelins and phosphatidylcholine), that showed positive correlations (all FDR p < 0.05) with DXA estimates of total and truncal fat (ρ = 0.11-0.19), skinfold measures (ρ = 0.09-0.26), and BMI and waist circumference (ρ = 0.15 and 0.18, respectively). These correlations were similar when stratified by sex. Within this module, sphingomyelin (d18:2/14:0, d18:1/14:1)*, a sphingomyelin sub-specie that is an important component of cell membranes, showed the strongest associations.
CONCLUSIONS
A module of metabolites was associated with adiposity measures in childhood.
PubMed: 38958048
DOI: 10.1111/ijpo.13149 -
Journal of the American Heart... Jul 2024Coronary atherosclerosis detected by imaging is a marker of elevated cardiovascular risk. However, imaging involves large resources and exposure to radiation. The aim...
BACKGROUND
Coronary atherosclerosis detected by imaging is a marker of elevated cardiovascular risk. However, imaging involves large resources and exposure to radiation. The aim was, therefore, to test whether nonimaging data, specifically data that can be self-reported, could be used to identify individuals with moderate to severe coronary atherosclerosis.
METHODS AND RESULTS
We used data from the population-based SCAPIS (Swedish CardioPulmonary BioImage Study) in individuals with coronary computed tomography angiography (n=25 182) and coronary artery calcification score (n=28 701), aged 50 to 64 years without previous ischemic heart disease. We developed a risk prediction tool using variables that could be assessed from home (self-report tool). For comparison, we also developed a tool using variables from laboratory tests, physical examinations, and self-report (clinical tool) and evaluated both models using receiver operating characteristic curve analysis, external validation, and benchmarked against factors in the pooled cohort equation. The self-report tool (n=14 variables) and the clinical tool (n=23 variables) showed high-to-excellent discriminative ability to identify a segment involvement score ≥4 (area under the curve 0.79 and 0.80, respectively) and significantly better than the pooled cohort equation (area under the curve 0.76, <0.001). The tools showed a larger net benefit in clinical decision-making at relevant threshold probabilities. The self-report tool identified 65% of all individuals with a segment involvement score ≥4 in the top 30% of the highest-risk individuals. Tools developed for coronary artery calcification score ≥100 performed similarly.
CONCLUSIONS
We have developed a self-report tool that effectively identifies individuals with moderate to severe coronary atherosclerosis. The self-report tool may serve as prescreening tool toward a cost-effective computed tomography-based screening program for high-risk individuals.
PubMed: 38958022
DOI: 10.1161/JAHA.124.034603 -
Frontiers in Cellular and Infection... 2024Wild rodents can serve as reservoirs or carriers of , thereby enabling parasite transmission to domestic animals and humans. This study aimed to investigate the...
INTRODUCTION
Wild rodents can serve as reservoirs or carriers of , thereby enabling parasite transmission to domestic animals and humans. This study aimed to investigate the prevalence of in wild rodents from the Inner Mongolian Autonomous Region and Liaoning Province of China. Moreover, to evaluate the potential for zoonotic transmission at the genotype level, a genetic analysis of the isolates was performed.
METHODS
A total of 486 wild rodents were captured from two provinces in China. Polymerase chain reaction (PCR) was performed to amplify the vertebrate () gene in the fecal DNA of the rodents to detect their species. The genotype of was determined PCR amplification of the internal transcribed spacer (ITS) region of rDNA. The examination of genetic characteristics and zoonotic potential requires the application of similarity and phylogenetic analysis.
RESULTS
The infection rates of in the four identified rodent species were 5.2% for (n = 89), 4.5% for (n = 96), 11.3% for (n = 106), and 38.5% for (n = 195). Infection was detected at an average rate of 17.4% among 486 rodents. Of the 11 identified genotypes, nine were known: SHR1 (detected in 32 samples), D (30 samples), EbpA (9 samples), PigEbITS7 (8 samples), HNR-IV (6 samples), Type IV (5 samples), HNR-VII (2 samples), HNH7 (1 sample), and HNPL-V (1 sample). Two novel genotypes were also discovered, NMR-I and NMR-II, each comprising one sample. The genotypes were classified into group 1 and group 13 phylogenetic analysis.
DISCUSSION
Based on the initial report, is highly prevalent and genetically diverse in wild rodents residing in the respective province and region. This indicates that these animals are crucial for the dissemination of . Zoonotic -carrying animals present a significant hazard to local inhabitants. Therefore, it is necessary to increase awareness regarding the dangers presented by these rodents and reduce their population to prevent environmental contamination.
Topics: Animals; Enterocytozoon; China; Genotype; Zoonoses; Microsporidiosis; Phylogeny; Rodentia; Host Specificity; Feces; Animals, Wild; Prevalence; Cytochromes b; Disease Reservoirs; Mice; DNA, Ribosomal Spacer; Humans; Rodent Diseases; Polymerase Chain Reaction; DNA, Fungal; Rats
PubMed: 38957795
DOI: 10.3389/fcimb.2024.1409685 -
ACS Sustainable Resource Management Jun 2024The need for sustainable agriculture amid a growing population and challenging climatic conditions is hindered by the environmental repercussions of widespread...
The need for sustainable agriculture amid a growing population and challenging climatic conditions is hindered by the environmental repercussions of widespread fertilizer use, resulting in the accumulation of metal ions and the loss of micronutrients. The present study provides an approach to improve the efficiency of nanofertilizers by controlling the release of copper (Cu) ions from copper oxide (CuO) nanofertilizers through bioionic liquids based on plant growth regulators (PGR-ILs). A 7-day study was conducted to understand the kinetics of Cu ion release in aqueous solution of five different PGR-ILs, with choline ascorbate ([Cho][Asc]) or choline salicylate ([Cho][Sal]) leading to 200- to 700-fold higher dissolution of Cu ions in comparison to choline indole-3-acetate ([Cho][IAA]), choline indole-3-butyrate ([Cho][IBA]), and choline gibberellate ([Cho][GA]). The tunable diffusion of Cu ions from CuO nanofertilizers using PGR-ILs is then applied in a foliar spray study, evaluating its impact on the growth phenotype, photosynthetic parameters, and carbon dioxide (CO) sequestration in in a greenhouse. The results indicate that nanoformulations with lower concentrations of Cu ions in PGR-IL solutions exhibit superior outcomes in terms of plant length, net photosynthetic rate, dry biomass yield, and CO sequestration, emphasizing the critical role of dissolution kinetics in determining the effectiveness of PGR-IL-based nanoformulations for sustainable agriculture.
PubMed: 38957680
DOI: 10.1021/acssusresmgt.4c00041 -
Ghana Medical Journal Sep 2023The study sought to determine clinical characteristics and histologic subtypes of a cohort of lung cancer patients in a tertiary facility.
OBJECTIVE
The study sought to determine clinical characteristics and histologic subtypes of a cohort of lung cancer patients in a tertiary facility.
DESIGN
Retrospective review of the medical records of histology-confirmed lung cancer cases at the respiratory clinic over a 3-year period.
SETTING
Respiratory Clinic, Korle-Bu Teaching Hospital, Accra, Ghana.
PARTICIPANTS
All adult patients with histologically diagnosed lung cancer were enrolled.
MAIN OUTCOME MEASURES
Lung cancer histological types.
RESULTS
The proportion of lung cancer cases was 12.4%. The majority were women (57.8%) and the mean age at diagnosis was 55.8±16.0 years. The patients were predominantly non-smokers (61%). Common symptoms were chronic cough and chest pain. More than two-thirds of the cases presented in clinical stages III and IV with the predominant histological subtype being adenocarcinoma in smokers and non-smokers. Genetic testing for epidermal growth factor receptor (EGFR) and Anaplastic Lymphoma kinase (ALK) mutations were largely absent.
CONCLUSIONS
The majority of lung cancer patients presented late with advanced disease. Adenocarcinoma was the predominant histological subtype in a predominantly non-smoking population, with an increased prevalence among women less than 60 years. This should encourage testing for genetic mutations to improve patient survival.
FUNDING
None declared.
Topics: Humans; Lung Neoplasms; Female; Middle Aged; Male; Retrospective Studies; Tertiary Care Centers; Aged; Adult; Ghana; Smoking; Adenocarcinoma; Neoplasm Staging; Cough; ErbB Receptors; Aged, 80 and over; Chest Pain
PubMed: 38957673
DOI: 10.4314/gmj.v57i3.2 -
Frontiers in Immunology 2024Targeted therapy and immunotherapy are both important in the treatment of non-small-cell lung cancer (NSCLC). Accurate diagnose and precise treatment are key in...
Targeted therapy and immunotherapy are both important in the treatment of non-small-cell lung cancer (NSCLC). Accurate diagnose and precise treatment are key in achieving long survival of patients. fusion is a rare oncogenic factor, whose optimal detection and treatment are not well established. Here, we report on a 32-year-old female lung adenocarcinoma patient with positive PD-L1 and negative driver gene detected by DNA-based next-generation sequencing (NGS). A radical resection of the primary lesion after chemotherapy combined with PD-1 checkpoint inhibitor administration indicated primary immuno-resistance according to her pathological response and rapid relapse. A rare was detected by RNA-based NGS, which was confirmed by fluorescence hybridization. Multiplex immunofluorescence revealed a PD-L1 related heterogeneous immunosuppressive microenvironment with little distribution of CD4+ T cells and CD8+ T cells. Savolitinib therapy resulted in a progression-free survival (PFS) of >12 months, until a new secondary resistance mutation in p.D1228H was detected by re-biopsy and joint DNA-RNA-based NGS after disease progression. In this case, fusion NSCLC was primarily resistant to immunotherapy, sensitive to savolitinib, and developed secondary p.D1228H mutation after targeted treatment. DNA-RNA-based NGS is useful in the detection of such molecular events and tracking of secondary mutations in drug resistance. To this end, DNA-RNA-based NGS may be of better value in guiding precise diagnosis and individualized treatment in this patient population.
Topics: Humans; Female; Adenocarcinoma of Lung; Adult; Lung Neoplasms; High-Throughput Nucleotide Sequencing; Proto-Oncogene Proteins c-met; Oncogene Proteins, Fusion; Drug Resistance, Neoplasm; Immune Checkpoint Inhibitors
PubMed: 38957460
DOI: 10.3389/fimmu.2024.1386561 -
Evolutionary Applications Jul 2024The deliberate release of captive-bred individuals, the accidental escape of domesticated strains, or the invasion of closely related conspecifics into wild populations...
The deliberate release of captive-bred individuals, the accidental escape of domesticated strains, or the invasion of closely related conspecifics into wild populations can all lead to introgressive hybridization, which poses a challenge for conservation and wildlife management. Rates of introgression and the magnitude of associated demographic impacts vary widely across ecological contexts. However, the reasons for this variation remain poorly understood. One rarely considered phenomenon in this context is soft selection, wherein relative trait values determine success in intraspecific competition for a limiting resource. Here we develop an eco-genetic model explicitly focussed on understanding the influence of such competitive interactions on the eco-evolutionary dynamics of wild populations experiencing an influx of foreign/domesticated individuals. The model is applicable to any taxon that experiences natural or human-mediated inputs of locally maladapted genotypes ('intrusion'), in addition to phenotype-dependent competition for a limiting resource (e.g. breeding sites, feeding territories). The effects of both acute and chronic intrusion depended strongly on the relative competitiveness of intruders versus locals. When intruders were competitively inferior, density-dependent regulation limited their reproductive success (ability to compete for limited spawning sites), which prevented strong introgression or population declines from occurring. In contrast, when intruders were competitively superior, this amplified introgression and led to increased maladaptation of the admixed population. This had negative consequences for population size and population viability. The results were sensitive to the intrusion level, the magnitude of reproductive excess, trait heritability and the extent to which intruders were maladapted relative to locals. Our findings draw attention to under-appreciated interactions between phenotype-dependent competitive interactions and maladaptive hybridization, which may be critical to determining the impact captive breeding programmes and domesticated escapees can have on otherwise self-sustaining wild populations.
PubMed: 38957310
DOI: 10.1111/eva.13746 -
Journal of Cellular and Molecular... Jul 2024A genome-wide association study (GWAS) is a powerful tool in investigating genetic contribution, which is a crucial factor in the development of complex multifactorial...
A genome-wide association study (GWAS) is a powerful tool in investigating genetic contribution, which is a crucial factor in the development of complex multifactorial diseases, such as type 2 diabetes mellitus. Type 2 diabetes mellitus is a major healthcare burden in the Western Pacific region; however, there is limited availability of genetic-associated data for type 2 diabetes in Southeast Asia, especially among the Kinh Vietnamese population. This lack of information exacerbates global healthcare disparities. In this study, 997 Kinh Vietnamese individuals (503 with type 2 diabetes and 494 controls) were prospectively recruited and their clinical and paraclinical information was recorded. DNA samples were collected and whole genome genotyping was performed. Standard quality control and genetic imputation using the 1000 Genomes database were executed. A polygenic risk score for type 2 diabetes was generated in different models using East Asian, European, and mix ancestry GWAS summary statistics as training datasets. After quality control and genetic imputation, 107 polymorphisms reached suggestive statistical significance for GWAS (≤5 × 10) and rs11079784 was one of the potential markers strongly associated with type 2 diabetes in the studied population. The best polygenic risk score model predicting type 2 diabetes mellitus had AUC = 0.70 (95% confidence interval = 0.62-0.77) based on a mix of ancestral GWAS summary statistics. These data show promising results for genetic association with a polygenic risk score estimation in the Kinh Vietnamese population; the results also highlight the essential role of population diversity in a GWAS of type 2 diabetes mellitus.
Topics: Humans; Diabetes Mellitus, Type 2; Genome-Wide Association Study; Male; Female; Polymorphism, Single Nucleotide; Vietnam; Genetic Predisposition to Disease; Multifactorial Inheritance; Pilot Projects; Middle Aged; Risk Factors; Asian People; Case-Control Studies; Aged; Adult; Genetic Risk Score; Southeast Asian People
PubMed: 38957036
DOI: 10.1111/jcmm.18526 -
Parasites & Vectors Jul 2024Toxoplasma gondii infection affects a significant portion of the global population, leading to severe toxoplasmosis and, in immunocompromised patients, even death....
BACKGROUND
Toxoplasma gondii infection affects a significant portion of the global population, leading to severe toxoplasmosis and, in immunocompromised patients, even death. During T. gondii infection, disruption of gut microbiota further exacerbates the damage to intestinal and brain barriers. Therefore, identifying imbalanced probiotics during infection and restoring their equilibrium can regulate the balance of gut microbiota metabolites, thereby alleviating tissue damage.
METHODS
Vimentin gene knockout (vim-/-) mice were employed as an immunocompromised model to evaluate the influence of host immune responses on gut microbiota balance during T. gondii infection. Behavioral experiments were performed to assess changes in cognitive levels and depressive tendencies between chronically infected vim-/- and wild-type (WT) mice. Fecal samples were subjected to 16S ribosomal RNA (rRNA) sequencing, and serum metabolites were analyzed to identify potential gut probiotics and their metabolites for the treatment of T. gondii infection.
RESULTS
Compared to the immunocompetent WT sv129 mice, the immunocompromised mice exhibited lower levels of neuronal apoptosis and fewer neurobehavioral abnormalities during chronic infection. 16S rRNA sequencing revealed a significant decrease in the abundance of probiotics, including several species of Lactobacillus, in WT mice. Restoring this balance through the administration of Lactobacillus murinus and Lactobacillus gasseri significantly suppressed the T. gondii burden in the intestine, liver, and brain. Moreover, transplantation of these two Lactobacillus spp. significantly improved intestinal barrier damage and alleviated inflammation and neuronal apoptosis in the central nervous system. Metabolite detection studies revealed that the levels of various Lactobacillus-related metabolites, including indole-3-lactic acid (ILA) in serum, decreased significantly after T. gondii infection. We confirmed that L. gasseri secreted much more ILA than L. murinus. Notably, ILA can activate the aromatic hydrocarbon receptor signaling pathway in intestinal epithelial cells, promoting the activation of CD8 T cells and the secretion of interferon-gamma.
CONCLUSION
Our study revealed that host immune responses against T. gondii infection severely disrupted the balance of gut microbiota, resulting in intestinal and brain damage. Lactobacillus spp. play a crucial role in immune regulation, and the metabolite ILA is a promising therapeutic compound for efficient and safe treatment of T. gondii infection.
Topics: Animals; Gastrointestinal Microbiome; Mice; Toxoplasma; Mice, Knockout; Brain Injuries; Probiotics; Brain; Lactobacillus; Disease Models, Animal; Immunocompromised Host; Toxoplasmosis; RNA, Ribosomal, 16S; Male; Intestines
PubMed: 38956725
DOI: 10.1186/s13071-024-06349-8